Abstract

OBJECTIVE:

We sought to assess the appearance of cerebral cavernous malformations (CCM) on magnetic resonance imaging (MRI) scans in murine Ccm1 and Ccm2 gene knockout models and to develop a technique of lesion localization for correlative pathobiological studies

METHODS:

Brains from 18 CCM mutant mice (Ccm1 Trp53 and Ccm2 Trp53) and 28 control animals were imaged by gradient recalled echo (T2*)-weighted MRI scans at 4.7- and 14.1-T in vivo and/or ex vivo. After MRI scanning, the brains were removed and stained with hematoxylin and eosin, and cells were laser-microdissected for molecular biological studies.

RESULTS:

T2*-weighted MRI scans of brains in vivo and ex vivo revealed lesions similar to human CCMs in mutant mice, but not in control animals. Stereotactic localization and hematoxylin and eosin staining of correlative tissue sections confirmed lesion histology and revealed other areas of dilated capillaries in the same brains. Some lesions were identified by MRI scans at 14.1-T, but not at 4.7-T. Polymerase chain reaction amplification from Ccm1 and beta-actin genes was demonstrated from nucleic acids extracted from laser microdissected lesional and perilesional cells.

CONCLUSION:

The high-field MRI techniques offer new opportunities for further investigation of disease pathogenesis in vivo, and the localization, staging, and histobiological dissection of lesions, including the presumed earliest stages of CCM lesion development.

Stereotactic drawings of views of mouse brain to locate CCM lesions. (A) Top view and midsagittal planes with locations of 1-mm serial anatomic coronal sections from the most caudal section at the cerebellar hindbrain to the olfactory bulbs at the frontal rostrum. (B) A coronal section divided into four quadrants: right dorsal (RD), left dorsal (LD), right ventral (RV) and left ventral (LV). (C) Location (arrows) and relative sizes of five lesions within the brain of a Ccm1+/-Trp53+/+ mouse determined by MR imaging ex vivo at 14.1 T.

CCM lesions within brains of two Ccm1+/-Trp53+/+ mice. Three dimensional gradient recalled echo MR imaging of a mouse brain in vivo at 4.7 T (A) and ex vivo at 4.7 T (C) and at 14.1 T (D). The section was stained with H&E (B). The CCM is indicated by arrows (A-D). Enlarged images of the lesion from this mouse (E-G) and from another mouse (H-J) include 3D reconstructions (E, H) and single slice (F, I) from gradient recalled echo MR acquired at 14.1 T field strength and corresponding histologic sections stained with H&E (G, J). Scale bars are 1 mm (A-D) and 0.5 mm (E-J).